Anti-mitotic agents such as taxanes (e.g., docetaxel) and vinca alkaloids (e.g., vinblastine or vincristine) are among the most effective drugs in treating metastatic diseases, but their benefits are limited by the rapid development of resistance. As such, there is still a need for selective therapeutic agents that not only target cell division and induce early cell death in the primary tumor but also suppress metastatic spread.
Dynamics of microtubules is an important aspect of cell growth. Stathmin (STMN1, OP18, Oncoprotein18) is a microtubule destabilizing protein that plays an important role in the anti-mitotic drug response as it regulates mitotic spindle dynamics involved in cell proliferation and migration/invasion. STMN1 acts directly on α-tubulin polymers in microtubules, promoting their destabilization and depolymerization. Cancer cells utilize STMN1 to accommodate rapid cell division and proliferation. Expression of STMN1 is controlled by common cell cycle regulators such as cyclin-dependent kinase-1 (CDK1), cdc2 kinase, p53 as well as apoptosis signal-regulating kinase 1 (ASK1). Inhibition of STMN1 with small interfering RNA (siRNA) was shown to sensitize cancer cells to 5-FU treatment. Additionally, knockdown of STMN1 blocked tumor growth in vivo in a model of pancreatic cancer. Ribozyme targeting of STMN1 was associated with G2/M arrest and apoptosis of Estrogen Receptor+(ER) and ER− breast cancer cells. However, overexpression of STMN1 blocked metastatic spread in prostate cancer cells and induced growth arrest at the G2/M phase checkpoint in various breast cancer cell lines. STMN1 is also a potential target for modulating tumor angiogenesis as it is a regulator of microtubule dynamics, Rho activity and vascular permeability.